1. Field of the Invention
The present invention generally relates to anticoagulants. More particularly, the invention provides sulfated bis-cyclic compounds that mimic the anticoagulant function of heparin.
2. Background Description
Heparin is widely used as an anticoagulant in the treatment of conditions requiring such an agent, e.g. as a “blood thinner” prior to invasive cardiac surgical procedures. Heparin is a linear co-polymer composed of alternating glucosamine and uronic acid residues. A heparin chain may contain anywhere from ˜10 to ˜80 of these saccharide residues, thus making a typical heparin preparation polydisperse. Further, these saccharide residues may be sulfated at various positions, thus making a typical heparin chain heterogeneous.
Commercially available heparin is a natural product obtained from either bovine or porcine sources (1). A commercial heparin preparation is thus a mixture of numerous polysaccharide species of different chain lengths and sulfate group distributions. Low-molecular-weight heparins (LMWH) have been prepared from the natural product through both enzymatic and chemical means. These heparins are preparations in which the average molecular weight of the parent polysaccharide has been selectively reduced from ˜14,000 to ˜5,000. However, LMWHs are still heterogenous and polydisperse. Further, while LMWH are in general structurally similar to parent heparin, they may contain chemical changes introduced by the method of preparation.
Thus, one drawback in the use of heparin or LMWH for clinical purposes is that, due to their inherent polydisperse and heterogeneous nature, commercial preparations for clinical administration are relatively ill-defined. As a result, attempts have been made to design and produce heparin replacements with defined compositions. For example, a specific pentasaccharide that mimics the action of heparin and LMWH is available. This pentasaccharide is a linear molecule consisting of 1→4 linked glucoamine and uronic acid residues that are sulfated at specific points. The pentasaccharide is obtained through chemical synthesis (2). Unfortunately, the synthesis of the pentasaccharide is a multi-step, intricate and low-yielding procedure. Similarly, small, non-sugar molecules that partially mimic the anticoagulant action of heparin have been described in the literature. These molecules belong to either the flavan or the flavone series of structures, and are sulfated flavan or flavone derivatives (3). However, these products also fail to exhibit the highly efficient anticoagulant properties of heparin (4).
The prior art has heretofore failed to provide an anticoagulant of defined composition that is as effective as heparin and conveniently obtained. There is thus an ongoing need to develop such alternative anticoagulant agents.